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【结 构 式】 
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【分子编号】17246 【品名】2,3-pyridinedicarboxylic acid; Quinolinic Acid 【CA登记号】89-00-9 |
【 分 子 式 】C7H5NO4 【 分 子 量 】167.12104 【元素组成】C 50.31% H 3.02% N 8.38% O 38.29% |
合成路线1
该中间体在本合成路线中的序号：(I)The anhydrization of pyridine-2,3-dicarboxylic acid (I) with acetic anhydride gives the corresponding anhydride (II), which by treatment with benzylamine (III) is converted into the benzylimide (IV). The hydrogenation of (IV) with H2 over Pd/C yields 8-benzyl-2,8-diazabicyclo[4.3.0]nonane-7,9-dione (V), which is further hydrogenated with LiAlH4, affording (?-cis-8-benzyl-2,8-diazabicyclo[4.3.0]nonane (VI) (1). The optical resolution of (VI) by separation of the cis-(R,R)-isomer as crystalline L-(+)-tartrate and further purification of the cis-(S,S)-isomer (VII) as the D-(-)-tartrate affords enantiomerically pure (S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane (VII). The debenzylation of (VII) by hydrogenolysis with H2 over Pd/C gives (S,S)-2,8-diazabicyclo[4.3.0]nonane (VIII), which is condensed with 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (IX) in basic medium and finally salified with HCl. The 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (IX) has been obtained as follows: The reaction of 2,4,5-trifluoro-3-methoxybenzoyl chloride (X) with malonic acid monoethyl ester monopotassium salt (XI) by means of triethylamine gives 2-(2,4,5-trifluoro-3-methoxybenzoyl)acetic acid ethyl ester (XII), which is condensed with triethyl orthoformate yielding the corresponding ethoxymethylene derivative (XIII). The reaction of (XIII) with cyclopropylamine affords the cyclopropylaminomethylene derivative (XIV), which is finally cyclized to (IX) by means of NaF in DMF.
| 【1】 Martel, A.M.; Leeson, P.A.; Castañer, J.; Bay-12-8039. Drugs Fut 1997, 22, 2, 109. |
| 【2】 Petersen, U.; Bremm, K.-D.; Dalhoff, A.; Endermann, R.; Heilmann, W.; Krebs, A.; Schenke, T.; Synthesis and in vitro activity of BAY 12-8039, a new 8-methoxy-quinolone. 36th Intersci Conf Antimicrob Agents Chemother (Sept 15-18, New Orleans) 1996, Abst. F1.. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 17246 | 2,3-pyridinedicarboxylic acid; Quinolinic Acid | 89-00-9 | C7H5NO4 | 详情 | 详情 |
| (II) | 17247 | furo[3,4-b]pyridine-5,7-dione; 2,3-Pyridinedicarboxylic anhydride | 699-98-9 | C7H3NO3 | 详情 | 详情 |
| (III) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (IV) | 17249 | 6-benzyl-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione | C14H10N2O2 | 详情 | 详情 | |
| (V) | 17250 | 6-benzyltetrahydro-1H-pyrrolo[3,4-b]pyridine-5,7(2H,6H)-dione | C14H16N2O2 | 详情 | 详情 | |
| (VI) | 17251 | 6-benzyloctahydro-1H-pyrrolo[3,4-b]pyridine | C14H20N2 | 详情 | 详情 | |
| (VII) | 17252 | (4aS,7aS)-6-benzyloctahydro-1H-pyrrolo[3,4-b]pyridine | C14H20N2 | 详情 | 详情 | |
| (VIII) | 17253 | (4aS,7aS)octahydro-1H-pyrrolo[3,4-b]pyridine | C7H14N2 | 详情 | 详情 | |
| (IX) | 12266 | 1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | 112811-72-0 | C14H11F2NO4 | 详情 | 详情 |
| (X) | 12259 | 2,4,5-Trifluoro-3-methoxybenzoyl chloride | C8H4ClF3O2 | 详情 | 详情 | |
| (XI) | 14338 | potassium 3-ethoxy-3-oxopropanoate | 6148-64-7 | C5H7KO4 | 详情 | 详情 |
| (XII) | 12261 | ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propanoate | C12H11F3O4 | 详情 | 详情 | |
| (XIII) | 12262 | ethyl (Z)-3-ethoxy-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate | C15H15F3O5 | 详情 | 详情 | |
| (XIV) | 12264 | ethyl (E)-3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate | C16H16F3NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(L)In a further procedure, pyridine-2,3-dicarboxylic acid (L) was esterified with MeOH and SOCl2 and then oxidized to the N-oxide (LI), which by treatement with POCl3 gave chloropyridine (LII). Then, substitution of the halogen atom of (LII) for a butyl group using n-BuLi in the presence of ZnCl2 and palladium catalyst provided butylpyridine (LIII). Saponification of the methyl esters, followed by reaction with Ac2O gave cyclic anhydride (LIV). This was condensed with organozinc reagent (LV) to give ketone (LVI). After activation of (LVI) with carbonyl diimidazole, condensation with the lithium enolate of ethyl acetate, followed by cyclization produced cyclopentenone (LVII). This was condensed with Grignard reagent (XXIV) to give (LVIII) and then reduced with Zn and HCl and isomerized in the presence of EtONa to provide (LIX) as a racemic mixture.
| 【1】 Niiyama, K.; et al.; A potent, orally active, most balanced ETA/ETB dual endothelin receptor antagonist. Discovery of J-104132. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.297. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIV) | 27570 | 1,3-benzodioxol-5-yl(bromo)magnesium | C7H5BrMgO2 | 详情 | 详情 | |
| (L) | 17246 | 2,3-pyridinedicarboxylic acid; Quinolinic Acid | 89-00-9 | C7H5NO4 | 详情 | 详情 |
| (LI) | 27595 | 2,3-bis(methoxycarbonyl)-1-pyridiniumolate | C9H9NO5 | 详情 | 详情 | |
| (LII) | 27596 | dimethyl 6-chloro-2,3-pyridinedicarboxylate | C9H8ClNO4 | 详情 | 详情 | |
| (LIII) | 27597 | dimethyl 6-butyl-2,3-pyridinedicarboxylate | C13H17NO4 | 详情 | 详情 | |
| (LIV) | 27598 | 2-butylfuro[3,4-b]pyridine-5,7-dione | C11H11NO3 | 详情 | 详情 | |
| (LV) | 27599 | [2-(benzyloxy)-4-methoxyphenyl](chloro)zinc | C14H13ClO2Zn | 详情 | 详情 | |
| (LVI) | 27600 | 2-[2-(benzyloxy)-4-methoxybenzoyl]-6-butylnicotinic acid | C25H25NO5 | 详情 | 详情 | |
| (LVII) | 27601 | ethyl 7-[2-(benzyloxy)-4-methoxyphenyl]-2-butyl-5-oxo-5H-cyclopenta[b]pyridine-6-carboxylate | C25H25NO5 | 详情 | 详情 | |
| (LVIII) | 27602 | ethyl 5-(1,3-benzodioxol-5-yl)-7-[2-(benzyloxy)-4-methoxyphenyl]-2-butyl-5-hydroxy-5H-cyclopenta[b]pyridine-6-carboxylate | C36H35NO7 | 详情 | 详情 | |
| (LIX) | 27603 | ethyl (5S,6R,7R)-5-(1,3-benzodioxol-5-yl)-7-[2-(benzyloxy)-4-methoxyphenyl]-2-butyl-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate | C36H37NO6 | 详情 | 详情 |